The excitatory amino acids, including glutamate, modulate a variety of physiological processes in the mammalian central nervous system (CNS), such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ionic channels. The second class is the G-protein or second messenger-linked “metabotropic” glutamate (mGluR) receptor. Both classes of receptors appear to mediate normal synaptic transmission along excitatory pathways, and also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
Various functionalized bicyclo[3.1.0]hexane derivative compounds have been recognized as mGluR modulators. The mGluR modulators are therapeutically useful for the treatment or prevention of psychiatric disorders, schizophrenia, anxiety and associated diseases, depression, bipolar disorder, and epilepsy; and neurological diseases, such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma. For example, U.S. Pat. No. 6,333,428, issued Dec. 25, 2001, discloses certain mGluR agonists which are 2-amino-6-fluorobicyclo[3.1.0]hexane derivatives of the formula below:
wherein R1 and R2 are each selected from the group consisting of
(1) hydrogen;
(2) C1-10 alkyl;
(3) C3-8 cycloalkyl; and
(4) C3-8 cycloalkyl-C1-5 alkyl;
and pharmaceutically acceptable salts thereof. The '428 patent states that the compounds of the invention may be in racemic form, or may be in enantiomeric form. The '428 patent also discloses certain novel intermediates of the formula below:
wherein R1 is as defined above.
U.S. Pat. No. 6,160,009, issued Dec. 12, 2000, discloses a class of functionalized bicyclo[3.1.0]hexane derivatives, which are therapeutically useful as mGluR agonists, of the formula below:
wherein R1 and R2 could together represent ═O.
U.S. Pat. No. 5,750,566, issued May 12, 1998, discloses an mGluR agonist of the formula below:
which is known as LY 354740.
Preparation of the mGluR modulators and intermediates disclosed above has been disclosed in the aforementioned patents, in Nakazato et al., J. Med. Chem., 2000, 43, 4893-4909, and in WO 02/00595 (which is published in English as EP 1 295 862). However, the disclosed syntheses involve drawbacks which make them unsuitable for large scale production. For example, the syntheses disclosed in the '428 patent and in Nakazato call for the preparation of racemic intermediates, which must then be subjected to complicated separation procedures involving HPLC, resulting in low productivity. Typically, the known synthetic methods also require the use of expensive and hazardous reagents, such as Pd(OAc)2 and (PhSe)2, which must be present in stoichimetric amounts, and CH2N2. The synthetic method of Nakazato also requires a harsh hydrolysis using H2SO4 at high temperatures (145° C.) for five days as the last step of the synthesis, resulting in a low yield, and requires a difficult isolation of the final product from a hydantoin derivative precursor.
It will be appreciated that the mGluR modulators disclosed in U.S. Pat. Nos. 6,333,428, 6,160,009 and 5,570,566, are useful as therapeutic agents. As such, there is a need for a development of a process for the preparation of these compounds, which is readily amenable to scale-up, uses cost-effective and relatively safe reagents, and is therefore capable of practical application to large scale manufacture.
Applicants have now discovered a novel synthesis of a class of enantiomerically pure functionalized bicyclo[3.1.0]hexane derivative mGluR modulators and of enantiomerically pure intermediate compounds.